tbuckley/cabot-search huggingface dataset:
Abstract 12531: Electrophysiological Mechanisms of Tachycardia-Induced Cardiomyopathy in Human Myocardium
Authors: Steffen Pabel, Maria Knierim, Thea Stehle, Arnold Pöppl, Gerd P Hasenfuss, Lars S Maier, Katrin Streckfuss Boemeke, Samuel Sossalla
Journal: Circulation (2022)

Introduction: Tachycardia-induced cardiomyopathy (TCM) is a reversible form of heart failure. However, the effects of persistent tachycardia leading to TCM in the human are less understood limiting appropriate management of patients with this underrecognized condition. This study investigated the electrophysiological mechanisms of TCM. Methods and Results: Tachycardic in vitro electrical stimulation (120 bpm versus 60 bpm control) of human specimen was performed. In human twitching ventricular trabeculae from patients with preexistent heart failure, tachycardia for 8h compromised systolic force, while diastolic tension and relaxation time were increased (n=6/8 patients each). Human iPSC-cardiomyocytes (iPSC-CM) of healthy donors were utilized as human model suitable for extended electrical pacing. After 24h of tachycardia, systolic Ca 2+ -transient amplitude of iPSC-CM was reduced, while diastolic Ca 2+ levels and cytosolic Ca 2+ elimination were not changed (Fura-2, n tachycardia/control=49/44 cells). 7d of tachycardia resulted in a progressive decline of Ca 2+ -transient amplitude together with an impaired Ca 2+ elimination (n=73/66) thereby demonstrating the progression of TCM. Sarcoplasmic reticulum (SR) Ca 2+ load (caffeine application) and SERCA activity (K sys -K caff ) were reduced after 7d of tachycardia (n=13/13). Besides an impaired SERCA activity, we could identify an increased diastolic SR Ca 2+ spark frequency after 7d of tachycardia (n=76/79) as another mechanism of reduced SR Ca 2+ load. In voltage clamp studies, I CaL density was reduced after 7d of tachycardia (n=11/12), which may further contribute to impaired systolic Ca 2+ -handling. Conversely, action potential duration was prolonged after 7d of tachycardia compared to control (n=19/21). As a potential explanation for prolonged action potentials however, late sodium current (I NaL ) was enhanced after 7d of tachycardia (n=26/19). Conclusions: This study demonstrates for the first time in human myocardium that persistent tachycardia induces early adverse electrophysiological remodeling that may underlie the progression of TCM. These findings may help to understand the pathophysiology of an underrated but prevalent disease
Abstract 12525: Synergistic Effects of Pitavastatin and Pemafibrate on Hepatic Steatosis and Inflammation in <i>Ldlr</i> <sup>+/-</sup> Mice Fed Fat Diet
Authors: Katsunao Tanaka, Masahiro Koseki, Takeshi Okada, Hiroyasu Inui, Chang Jiuyang, Takashi Omatsu, Ayami Saga, Tohru Ohama, Makoto Nishida, Yasushi Sakata
Journal: Circulation (2022)

Introduction: The combination therapy of statin, ezetimibe and PCSK9 inhibitors enables us to reduce serum LDL-C and risk of atherosclerotic diseases. However, there remain patients who cause cardiovascular diseases. Recently, it has been reported that nonalcoholic fatty liver disease (NAFLD) might be a background for cardiovascular diseases. However, there are few reports on the combination therapy of statin and pemafibrate on hepatic steatosis and inflammation. Hypothesis: The aim of this study is to examine the impact of statin and/or pemafibrate on hepatic lipid contents and inflammatory gene expression in Ldlr +/- mice. Methods: Eight to ten weeks old male Ldlr +/- mice were used. Mice were fed high fat diet (HFD) ± 0.01% pitavastatin ± 0.00003% pemafibrate for four weeks. Serum lipids and liver histology/ lipid contents/ mRNA expression in four groups were examined. Results: Pemafibrate reduced serum triglycerides, particularly chylomicron and VLDL fractions, and increased HDL-C as previously reported. Hepatic triglyceride was unchanged, and very importantly, hepatic cholesterol and free-cholesterol were decreased with pitavastatin + pemafibrate compared to pitavastatin (pitavastatin vs pitavastatin + pemafibrate: cholesterol; 13.5±4.7 vs 9.4±1.9 mg/g of liver, P&lt;0.01, free-cholesterol; 10.4±4.8 vs 6.9±1.4 mg/g of liver, P&lt;0.01). The addition of pemafibrate resulted in a 46% increase in Cyp7a1 mRNA expression, suggesting that cholesterol in liver was reduced due to enhanced cholesterol excretion. Tnfa mRNA in liver was reduced by 62% and F4/80 staining of the liver showed decreased macrophage infiltration. Conclusions: Adding pemafibrate to pitavastatin did not alter hepatic triglyceride, however decreased cholesterol and free-cholesterol and improved inflammatory gene responses in liver, suggesting that the synergistic effect of pitavastatin and pemafibrate may be beneficial in NAFLD related atherosclerotic patients.
Abstract 12155: Trends in Catheter Ablation of Ventricular Tachycardia in Patients With Ischemic and Nonischemic Cardiomyopathy: A National Inpatient Sample Trend in the Years 2016-2019
Authors: Bruce Ferraro, Ei Ei Thwe, Kashyap Shah, Vivek Modi, Steven Stevens, Jamshid Shirani
Journal: Circulation (2022)

Introduction: Catheter ablation of ventricular tachycardia (CAVT) has emerged as a viable option in structural heart disease. Recent studies report differences in outcomes of CATV in ischemic (ICM) and non-ischemic (NICM) cardiomyopathy. We aimed to examine temporal trends and in-hospital outcomes of CATV in ICM and NICM. Methods: National Inpatient Sample 2016-2019 was queried using ICD-10 codes to identify adults with ICM or NICM who underwent CAVT. Temporal trends were assessed using logistic regression. Results: 193895 CAVT were performed between 2016 and 2019. CAVT increased in numbers for both ICM [16415 in 2016 to 23030 in 2019 (P&lt;0.001)] and NICM [22915 in 2016 to 31355 in 2019 (P&lt;0.001)] during this period. Overall, rate of most common in-hospital complications increased during study period (7.4% in 2016 to 9.2% in 2019, p&lt;0.0001) particularly of cardiogenic shock (3% in 2016 to 4.2% in 2019, p&lt;0.001) and pericardial effusion (2.9% in 2016 and 3.7% in 2019, p&lt;0.001). In concordance with higher rates of complications over time, there was also an increase in the rate of comorbid conditions as indicated by the Charlson’s Comorbidity Index Score &gt;3 (35% in 2016 and 40% in 2019, p&lt;.0001). Differences existed in the rate of most common in-hospital complications between ICM and NICM patients including cardiogenic shock (5%-vs-2.6%), pericarditis (1.3%-vs-2.1%), pericardial effusion 2.6%-vs-3.7%), and cardiac tamponade 1%-vs-1.5%) [all p&lt;0.001). In-patient mortality and length of stay were higher in those with ICM (1.6%-vs-0.8%; and 6.3-vs-4.9 days; both p&lt;0.001). Conclusions: The number of VT ablations for structural heart disease has increased in recent years. These promising procedures are performed with reasonable complication rates in progressively more complex settings. Differences exist in rates of complications between patients with ICM and NICM including in-hospital mortality.
Abstract 12573: Step Count, Self-Reported Physical Activity, and Five-Year Risk for Incident Atrial Fibrillation
Authors: Ayelet Shapira-Daniels, Jelena Kornej, Nicole L Spartano, Xuzhi Wang, Yuankai Zhang, Chathurangi H Pathiravasan, Chunyu Liu, Ludovic Trinquart, Belinda Borrelli, David D McManus, JoAnne Murabito, Emelia J Benjamin, Honghuang Lin
Journal: Circulation (2022)

Background: Obesity and sedentary lifestyles are known risk factors for atrial fibrillation (AF). Wearable devices such as smartwatches present an opportunity to investigate relations between daily step count and AF risk. Hypothesis: Higher daily step count, as measured by wearable devices, will be associated with a smaller five-year risk of AF, as predicted by CHARGE-AF score. Methods: Participants from the electronic Framingham Heart Study (eFHS) utilized an AppleWatch. Individuals with diagnosed AF were excluded. Daily step count, watch wear time (hours, days), and self-reported physical activity were collected. Individual five-year risk of AF was estimated using The Cohorts for Heart and Aging Research in Genomic Epidemiology AF (CHARGE-AF) score. Relation between daily step counts and five-year predicted AF risk was examined with linear regression adjusted for age, sex, and wear time. Secondary analyses examined effect modification by sex and obesity (body mass index ≥30 kg/m 2 ), as well as relation between self-reported physical activity and predicted 5-year AF risk. Results: We examined 932 eFHS participants (mean age 53±9 years, 61% female) with a median daily step of 7360 (25 th -75 th percentile 5841-9060). Most participants (89.2%) had &lt;2.5% CHARGE-AF risk. Every 1000 steps were associated with 0.08% lower CHARGE-AF risk ( P &lt;0.001). A stronger association was observed in men and individuals with obesity. In contrast, self-reported physical activity was not associated with CHARGE-AF risk. Conclusion: Higher daily step count was associated with lower predicted 5-year risk of AF, and this relation was stronger in men and participants with obesity. The utility of a wearable daily step counter for risk reduction for AF merits further investigation.
Abstract 11117: Phase 1 Danon Disease Results: The First Single Dose Intravenous (IV) Gene Therapy (RP-A501) With Recombinant Adeno-Associated Virus (AAV9:LAMP2B) for a Monogenic Cardiomyopathy
Authors: Joseph Rossano, Matthew Taylor, Kimberly Lin, Shilpi Epstein, Pavan Battiprolu, David Ricks, Abigail Waldron, Jonathan Schwartz, Barry Greenberg
Journal: Circulation (2022)

Background: Danon disease (DD) is a rare X-linked monogenic cardiomyopathy and multisystemic disorder caused by mutations in the LAMP2 gene. Male DD patients (pts) develop severe progressive hypertrophic cardiomyopathy (HCM), left ventricular (LV) dysfunction and arrhythmias resulting in a median mortality below age 20 years (y). Methods: This open-label, single-dose, phase 1 trial enrolled male DD pts with a LAMP2 mutation and cardiomyopathy in two age groups: ≥15 y and 8-14 y. Pts received IV infusion of RP-A501, an adeno-associated virus with a normal copy of the human LAMP2B gene (AAV9:LAMP2B), at doses of 6.7 x 1013 GC/kg (low dose) and 1.1 x 1014 GC/kg (high dose). Immunomodulation (IM) included prednisone and rituximab, with additional sirolimus for the most recently treated pediatric pts. Results: Between June 2019 and March 2022, 7 males with DD age 11.7 - 21.1y (median 18.3y; N=5 adult and N=2 pediatric) received RP-A501 (N=5 low dose and N=2 high dose). 83% of pts were NYHA Class II; one was NYHA Class III. IM compliance was confirmed in 6/7 pts. All pts are alive and stable at 3-30 months (m) follow-up. One adult pt with baseline LV systolic dysfunction required heart transplant at 5m post RP-A501, most likely related to DD progression. All adverse events (AEs) related to RP-A501 or IM were manageable and reversible. No RP-A501-related SAEs were observed in the pediatric pts. On baseline endomyocardial biopsy, no pts had significant LAMP2B expression; 100% (N=6/6) of evaluable pts had cardiac LAMP2B expression within 6m of therapy with improved myocardial structure in 5/6. Pts evaluable beyond 6m had stabilized or improved BNP (N=5/5), troponin (N=5/5), and LV ejection fraction (N=5/5) by 6-12m, and stabilized/improved LV wall thickness (N=4/4) and NYHA Class (N=4/4) by 12-18m. These findings persist up to 30m post RP-A501. Conclusions: Results from this phase 1 trial in DD demonstrate that B- and T-lymphocyte directed immunomodulation enables safe IV RP-A501 gene therapy administration, resulting in cardiomyocyte transduction, LAMP2B expression, improved autophagy, and improved/stabilized serologic, echocardiographic and clinical parameters associated with survival in HCM. Updated results will be presented.
Abstract 11319: Post-Operative Dialysis in Failing Fontan Patients Undergoing Heart Transplant: How Well Does the Pre-Transplant Creatinine Clearance Risk-Stratify Patients?
Authors: Humera Ahmed, John Dykes, Sharon Chen, Maryanne Chrisant, Kevin P Daly, Rebecca K Ameduri, Kenneth R Knecht, Marc Richmond, Marc E Richmond, Kimberly Y Lin, Simon Urschel, Jacob Simmonds, KATHLEEN SIMPSON, Kurt Schumacher, Christopher S Almond
Journal: Circulation (2022)

Introduction: The need for dialysis early post-heart transplant (HT) can be suprisng when it occurs in the setting of purportedly normal renal function pre-HT, as has been described in failing Fontan (FF) patients. Hypothesis: We hypothesized that FF patients may have an increased incidence of post-operative dialysis (POD). Methods: The Pediatric Heart Transplant Society (PHTS) database was used to identify all children ≥2 years of age with failing Fontan (FF) physiology or cardiomyopathy (CM, benchmark lesion) who underwent isolated HT from 2005-2019. The primary endpoint was POD, defined as any form of dialysis within the first 30 days post-HT. Pre-transplant estimated glomerular filtration rate (eGFR) was calculated using the modified Schwartz formula, and a subset of patients with provided supplemental data additionally had renal function evaluated by a non-creatinine-based method. Results: Of 2003 children who met the inclusion criteria, 263 had FF (13%) and 1740 had CM (87%). Whereas the mean ages were similar (FF 11.2 vs CM 12.2 years, P=0.3), FF patients were 11% shorter (134 vs. 148, P&lt;0.001) and 9 kg lighter (31.2 vs. 40.2, P&lt;0.001), and had a lower serum creatinine (0.57 vs. 0.64 mg/dl, P=0.001) but similar eGFR pre-transplant (110.2 vs. 106.7 L/min/1.73m 2 , P=0.26). In a subset of 22 FF patients with available results from 24-hour urine collection or nuclear medicine scan, the Schwartz formula overestimated the GFR in 15/22 patients by an average of 40.2 ml/min/1.73 m2 (range 2.6 to 91.8). Overall, compared to CM patients, FF patients had a 4.7-fold higher risk of requiring POD (3.8% vs. 0.8%, P&lt;0.001). Of those who required POD, the difference in 30 day post-HT mortality was not significant (40% vs. 14%, 0.3). Multivariable analysis revealed that pre-HT ECMO and longer CPB times were independently associated with POD; there was a trend toward association of higher pre-HT eGFR (P=0.06). Conclusions: Fontan patients have a ~5-fold higher risk of post-operative dialysis compared to cardiomyopathy patients, and despite a normal or even supraphysiological pre-transplant estimated CrCl. Non-creatinine-based methods independent of malnutrition status should be considered in the FF population.
Abstract 11956: Blood DNA Methylation Predicts Differential Metabolic Outcomes Induced by Different Types of Weight-Loss Intervention: Findings From an Epigenome-Wide Association Study
Authors: Xiaoxiao Wen, Helena Palma-Gudiel, Guanhong Miao, Mingjing Chen, Zhiguang Huo, Hao Peng, Stephen Anton, Gang Hu, Ricky Brock, Phillip J Brantley, Jinying Zhao
Journal: Circulation (2022)

Background Previous epigenetic studies in obesity interventions have focused on the intervention-associated DNA methylation (DNAm) changes, yet whether the DNAm before intervention could be used as a predictor of prognosis has not been investigated. Here we hypothesize that baseline DNAm can predict differential metabolic outcomes, i.e., changes in fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c), induced by different weight-loss interventions. Methods The analyses included 75 individuals with obesity in the HeadsUp Study, a longitudinal study assessing the effectiveness of different weight-loss interventions, from the non-surgical intensive medical intervention (IMI), adjustable gastric band (BAND) and Roux-en-Y gastric bypass (RYGB) groups (n = 25 per group). Genome-wide DNAm was determined using baseline blood samples, while changes in FPG and HbA1c were measured at 1-year follow-up. Epigenome-wide association studies were performed on 455,983 CpGs to identify DNAm predictors of differential metabolic outcomes, adjusting for age, sex, BMI, FPG/HbA1c at baseline, weight loss and batch effect. Results DNAm levels at 3,216 and 117 CpG loci significantly predicted differential changes in FPG and HbA1c, respectively, when comparing RYGB vs. IMI groups, but not in other group comparisons (RYGB vs. BAND or BAND vs. IMI, with the exception of 6 CpGs identified for HbA1c changes when comparing RYGB vs. BAND), after FDR correction for multiple testing. Of these, altered DNAm at 79 CpGs significantly predicted changes in both FPG and HbA1c (RYGB vs. IMI). These CpGs were annotated to 68 genes, among which the most significant ones were SNX18, LNPK, CCDC178, ADAM7 and ZNF23 . These genes are mostly involved in adaptive thermogenesis, temperature homeostasis and regulation of cell population proliferation. Conclusions To our knowledge, this is the first study demonstrating that baseline blood DNAm predicts differential metabolic outcomes induced by different types of weight-loss interventions, independent of weight loss. Such results help explain, at least partly, the favorable metabolic outcomes of RYGB over other types of weight-loss intervention (e.g., BAND, IMI), and are likely to lead to precision strategies for obesity treatment.
Abstract 12556: Prevalence of Hypertension and Left Ventricular Hypertrophy in Adolescents Following Left Ventricular Outflow Tract Obstruction Repair
Authors: Aaron Walsh, Kan N Hor, Marc Lee, Simon Lee, Andrew H Tran
Journal: Circulation (2022)

Introduction: Left ventricular outflow tract obstructions predispose patients to increased lifetime risk of cardiovascular events even after successful repair (rLVOTO). Left ventricular hypertrophy (LVH) is an adaptive response to elevated afterload and is a predictor of cardiovascular events in adulthood. The prevalence of elevated blood pressure (SBP) and LVH in youths with rLVOTO is limited. Methods: Retrospective analysis of rLVOTO patients between 2012-2019, age 13-17 years with documented body mass index (BMI), SBP, LVOT velocity and left ventricular mass indexed to height (LVMi). Moderate LVOTO was defined as peak velocity ≥ 3 m/s. Patients categorized into normotensive (NT, SBP &lt; 120 mm Hg), elevated (E-BP, 120 ≤ SBP &lt; 130 mm Hg), Stage 1 HTN (HTN-1, 130 ≤ SBP &lt; 140 mm Hg) and Stage 2 HTN (HTN-2, SBP ≥ 140 mm Hg). Prevalence of LVH was reported in each group (pediatric cutoff of LVMi-HT 2.7 ≥ 38.6 g/ht 2.7 ). Results: A total of 193 patients met criteria (age 15.6 ± 1.4 years), 135/193 (70%) male, SBP 120±13 mm Hg, and LVMi-HT 2.7 36.2±9.8 g/ht 2.7 . Half were in the NT group (93/193 (48%)), 55/193 (28%) in E-BP, 32/193 (17%) in HTN-1, and 13/193 (7%) in HTN-2 with no difference in BMI. Prevalence of LVH increased with higher SBP with 24/93 (26%) in NT, 21/55 (38%) in E-BP, 14/32 (43%) in HTN-1, and 4/13 (31%) in HTN-2. 124/193 (64%) had no residual LVOT gradient, 69/193 (36%) with residual LVOT gradient. 52/69 (75%) had LVOT &lt; 3 m/s, of these 12/52 (23%) had ≥ HTN-1. 17/69 (25%) had residual LVOTO ≥ 3 m/s, of these 6/17 (35%) had ≥ HTN-1. No difference in LVMi found between no or mild LVOTO groups (35.9±13 vs 35.6±10 g/ht 2.7 , p = NS). Higher LVMi was found in the LVOTO ≥ 3 m/s group (41.5±13 g/ht 2.7 , p = 0.01 compared to both no or mild LVOTO). Conclusions: Youths with rLVOTO have a high prevalence of elevated BP, HTN, and LVH. When stratified by LVOTO severity, presence of ≥ HTN-1 was common with increased LVMi. No difference in BMI was observed among abnormal SBP groups suggesting BMI is not solely responsible for the increased LVMi. Longitudinal studies are needed to define the impact of rLVOTO and HTN on LVH over time. Our findings support early surveillance and management of hypertension in patients following LVOTO repair to help minimize the risk of future cardiovascular events related to LVH.
Abstract 12584: The Role of Toll-Like Receptor 3 in the Development of Aortic Valve Stenosis
Authors: Nicola Willemsen, Sven Niepmann, Ann Sophie Boucher, Georg Nickenig, Sebastian Zimmer
Journal: Circulation (2022)

Background: Our current concept of aortic valve stenosis (AS) development suggests that local chronic inflammation drives fibrosis and calcification of the valve cusps. This remodeling is driven by endothelial to mesenchymal transition (EndMT) of valvular endothelial cells (VECs) and by calcification of valvular interstitial cells (VICs). In a preliminary screening, we found Toll-like receptor 3 (TLR3) expression increased in human AS samples. Therefore, aim of this study was to investigate the role of TLR3 in the pathogenesis of AS. Methods/Results: We confirmed TLR3 expression in cultured human VICs and VECs. Upon specific TLR3 stimulation with PolyI:C, both VICs and VECs displayed a positive feedback with increased TLR3 expression. Concomitant treatment of PolyI:C-stimulated VICs and VECs with the TLR3/RNA complex inhibitor (C4a) significantly blunted this response. Importantly, the TLR3-mediated pro-inflammatory and calcifying response of VICs and EndMT by VECs was significantly reduced by TLR3-inhibtion with C4a.To examine the role or TLR3 in AS development, a wire injury induced AS mouse model was used. Valves were explanted and stained with hematoxylin/eosin, Sirius red, von Kossa, or anti CD68. PolyI:C treatment promoted AS, as demonstrated by increased valve cusp thickness and pronounced valvular inflammation. Interestingly, AS development was nearly absent in TLR3 deficient mice suggesting a critical role of endogenous TLR3 ligands in this model. Treatment of mice with C4a after wire-injury of the aortic valve significantly reduced both morphological and functional parameters of AS development. Conclusion: These findings not only support the role of endogenous TLR3 activation in the development of AS but suggest that specific TLR3 inhibition might be beneficial for the treatment or prevention of AS. Further studies are required to decipher the exact mechanisms how TLR3 contributes to AS.